Magnetic resonance imaging (MRI) is an imaging technique used primarily in clinical settings to produce very clear, detailed pictures of internal organs and tissues. These pictures are much more detailed than those from other scanning techniques. MRI began as a tomographic imaging method which produced an image of only a thin slice of the human body; however, MRI has advanced beyond this to become a volume imaging technique. The quality of images obtained using MRI can be increased by the i.v. administration of a contrast agent prior to the MRI exam. Contrast agents allow particular organs or tissues to be visualized more clearly by increasing the signal level of the particular organ or tissue relative to that of its surroundings.
One important application of magnetic resonance imaging is the visualization of tumors. One approach to obtaining high quality tumor images involves the use of antibodies that bind to the tumor cell. In one variant of this technique, a non-radiolabeled antibody is administered and allowed to localize and clear from the circulation followed a low molecular weight radiolabeled agent with high affinity for the pretargeted antibody (Paganelli, G. et al., J. Nucl. Med Comm. 12:211-234 (1991); Green, N M Biochem. J. 89:585-91 (1963); Hnatowich D J et al., J. Nucl. Med. 28:1294-1302 (1987)). Avidin, a cationic glycoprotein found in egg whites, has been used in tumor imaging in conjunction with biotin, a naturally occurring vitamin. Avidin has a very high affinity for biotin and is capable of binding four biotin molecules forming an avidin-biotin complex (Kd=10.sup.-15 M).
Two basic approaches for targeting tumors with the avidin-biotin system have been used in patients and animals. In the first method, avidin (or streptavidin)-conjugated antibodies are injected and days later when antibody-tumor binding is maximized, a radioactive biotin derivative is injected to localize the tumor. Unfortunately, incomplete clearance of unbound antibody from the blood can obscure visualization of the target site. In the second method, blood background is reduced by injecting biotinylated antibodies followed three days later by cold avidin. The resultant circulating biotinylated antibody-avidin complexes are sequestered from the blood by the liver. Radioactive biotin is then injected which binds to the antibody-biotin-avidin complexes already localized in the tumor. However, by employing “pretargetting” steps, both approaches for targeting tumors require that a subject be available to undergo multiple procedures over the course of a few days. A study by Morrel et al., reported uptake of In-111 labeled IgG and human serum albumin (HSA) in an E. coli infected rat model. The accumulation of both labeled proteins was found to be sufficient to produce clear images of the infection site (Morrel, E M et al., J. Nucl. Med. 30:1538-1545 (1989). In addition, the current biotin-avidin system suffers from slow target concentration and suboptimal target to non-target binding ratios which prevent acquisition of high-quality images owing to poor contrast and resolution. Therefore, a need exists for robust imaging agents that bind with high specificity to tumor tissue to produce high-quality images.
In addition to obtaining high quality images in order to better treat cancer and other diseases, the successful recovery from an illness generally requires treating the patient with a therapeutic drug. One particularly problematic aspect of administering a pharmaceutical compound is the delivery of the compound to the desired tissue in the patient. This can be especially true in the treatment of canerous tissue by administration of a radionuclide. The radionuclide functions by releasing radiation which causes cells to die, hence, the radionuclide needs to be delivered quickly and specifically to the cancerous tissue to avoid harming healthy tissue. In response to this need, many strategies and materials have been developed to safely deliver a drug to diseased tissue. However, the need still exists to deliver pharmaceutical agents to diseased tissue with high selectivity.